I propose that in depression, excessive rumination and dysregulated arousal serve to undermine general cognitive ability and functioning. I aim to explore this hypothesis at the behavioral and neural level. Rumination is a core feature of depression (Nolen-Hoeksema 2000), and predicts numerous indices of depressive psychopathology (Miranda and Nolen-Hoeksema 2007). Aim 1: Default mode network activation will be associated with rumination, and increased in depression. I propose that rumination, as reflected in hyperactivity of the default mode network, interferes with the functioning of a task-positive network underpinning correctly-performed demanding cognitive activity. Aim 2: During correct trials, default mode network hyperactivity will correlate with attenuated task-positive network activity in depression. I propose that arousal is dysregulated in depression, manifested in clinical symptoms such as diminished interest, fatigue, psychomotor agitation/retardation, and insomnia/hypersomnia, and will result in abnormal psychophysiological and neural responses to arousing events, such as errors on a cognitive task. Aim 3. During error trials, neural and psychophysiological measures of arousal will be increased in depression. Finally, I propose that dysregulated arousal also correlates with attenuated optimal functioning of the taskpositive network. Aim 4. During post-error trials, arousal-based enhancement of the task-positive network will be attenuated in depression. This application would test these hypotheses using a) an attentional task (Eriksen flanker task); b) multimodal imaging, including rapid presentation event-related functional magnetic resonance imaging (er-fMRI) and high density (128 channel) electroencephalography (EEG); c) concurrent psychophysiological indices (pupillometry); and d) measures of symptomatogloy and propensity to ruminate. We propose to recruit 30 patients with major depresive disorder (MOD) and 30 healthy control subjects. With 10-25% lifetime prevalence, high mortality (8th leading cause of death in the US in 1997), and a very high economic cost for society ($44 billion in the US in 1990), major depressive disorder (MDD) is a significant public health problem. We posit that dysregulation of networks involved in rumination, arousal and cognition are fundamental to the pathophysiology of depression. Characterization of this dysfunction could improve new neurotherapeutic treatments, such as repeated transcranial magnetic stimulation (rTMS,) for a disorder with such high individual and societal costs. [unreadable] [unreadable]